Novel 6,6-dihalo-9beta,10alpha-steroids



Sept. 23, 1969 P. WESTERHOF ET AL 3,468,917

NOVEL 6 G-DIHALO-SBP lOK-STEROIDS Filed June 27, 1966 a C=O HBC O z C=OBY l 9 (2H3 9+ g-0 a c=o 1 c=0 I 0 INVENTORS PIETER WESTERHOF HENDRIK EL. SCHOLER 3,468,917 NOVEL 6,6-DlHALO-9/3, Illa-STEROIDS lieterWesterhof and Hendrik Frederik Louis Scholer, Van Houtenlaan, Weesp,Netherlands, assignors, by mesne assignments, to US. PhilipsCorporation, New York, N.Y., a corporation of Delaware Filed June 27,1966, Ser. No. 560,484 Claims priority, application Great Britain, June30, 1965, 27,735/65 Int. Cl. C07c 169/66, 169/30; A61k 27/00 US. Cl.260-3973 15 Claims ABSTRACT OF THE DISCLOSURE Novel 6,6-dihalo-9fi, 10asteroids of the androstane and pregnane series such as6-brorno-6-chloro-l7a-hydroxy- 9 3,10a-pregn-4-en-3,20-dione 17-acetateand 6-bromo-6- fluoro-l7B-hydroxy-95,l0aandrost-4-en-3-one 17-acetate.These compounds have hormonal activities.

This invention relates to steroid compounds, and is concerned with a newclass of such compounds and methods of producing the same, and withprocesses using such compounds as starting materials or intermediatesfor the production of further compounds. In the ensuing description,reference is made to the accompanying drawings wherein are set outcertain structural chemical formulae, serially numbered foridentification.

The invention comprises a class of new steroid compounds, beingcompounds of Formula I shown in the accompanying drawings, in whichformula R represents a -COCH group, in which case R q representshydrogen or an esterified, etherified, or free hydroxy group, or

R represents an esterified, etherified or free hydroxy group in whichcase R' represents hydrogen or a lower alkyl, alkenyl or alkynyl groupcontaining from 1-6 carbon atoms,

Hal represents a fluorine, chlorine or bromine atom and Hal represents afluorine, chlorine or bromine atom,

and in which formula a double bond may be present between the carbonatoms 1 and 2.

The invention comprehends compounds of the aforesaid formula as defined,both of the so-called normal series of steroids, and of the 95, 100:series. This, and the optional presence of a A double bond, are denotedin the formula by the presence of both solid and dash-lines representingthe 1-2 and the 18-10 bonds, and the bond connecting the hydrogen atomat the 9-position to the nucleus.

The configuration at the asymmetric carbon atoms 8, 9, 10, 13 and 14 maybe either the same as in normal steroids or the same as in 9 8,IDOL-steroids. These configurations are 8 3, 9a, 10,8, 135, 14cc and 85,9,8, 1001, 135, 140:, respectively. Hereinafter, steroids showing thelatter configuration will be denoted 9B, IOa-steroids, whereas the otherso-called normal, steroids will be indicated without the use of any suchprefix. The notation (913, 10a) is used to indicate that members of bothseries are meant.

Particularly interesting compounds are those compounds of Formula I inwhich Hal and Hal each represents a fluorine atom.

The invention includes methods of preparing the aforesaid compounds ofFormula I, as will be further described below, and also pharmaceuticalpreparations comprising the same and methods of manufacturing suchpreparations comprising mixing the same with, or dissolving ordispersing in, a solid or liquid pharmaceutical carrier, if desiredtogether with other ingredients.

nited States Patent ice An esterified hydroxy group represented by R orR' in the above formula may be an acyloxy group containing from one totwenty carbon atoms. The acyl part of the acyloxy group is preferablythe acyl group of a saturated or unsaturated aliphatic mono-, diortricarboxylic acid, a mixed aliphatic-aromatic carboxylic acid, anaromatic carboxylic acid, or a saturated or unsaturated alicyclicormixed aliphatic-alicyclic monocarboxylic acid, especially those havingfrom 1-6 carbon atoms. Examples of suitable acyloxy groups are:formoxy-, acetoxy-, propionoxy-, or butyroxy-; acyloxy groups derivedfrom oleic acid, palmitic acid, stearic acid, enanthic acid, undecanoicacid, caproic acid, pivalic acid, succinic acid, malonic acid, citricacid; or from benzoic acid or p-hexyloxy-phenylpropionic acid,hexahydrobenzoic acid, phenylacetic acid, fi-cyclopentylpropionic acid,or fi-cyclohexylpropionic acid.

An etherified hydroxy group represented by R or R' q may be an alkoxygroup containing from one to ten carbon atoms. The alkyl part of thealkoxy group is preferably an aliphatic, alicyclic, mixedaliphatic-aromatic or mixed aliphatic-alicyclic group. Examples ofsuitable alkoxy groups are: methoxy-, ethoxy-, propoxy-, tert-, butoxy-,cyclopentyloxy-, cyclohexyloxy and benzyloxy, or methyl cyclopentyloxygroups.

The compounds according to the invention show surprising pharmacologicalproperties, in particular in influencing, the normal balance of hormonalactivities.

Thus, 6,6-difluoro-9B, l0a-pregn-4-en-3,20-dione (Formula II) showsovulation inhibiting activities and 6,6-difluoro-l7fi-hydroxy-9p,10-androst-4-en-3-one 17- acetate (Formula III) has anabolic andgonadotrophineinhibiting properties in particular with males.

Other interesting compounds within the scope of the invention include:

6-bromo-6-chloro-l7a-hydroxy-9/8,10a-pregn-4-en-3 ,20-

dione 17-acetate (Formula IV)6-bromo-6-fluoro-9fi,10a-pregn-4en-3,20-dione (Formula6-bromo-6-fiuoro-l7a-hydroxy-9B,lOu-pregn-4-en-3,20-

dione l7-acetate (Formula VI) 6 -bromo-6-fluoro-17,3-hydroxy-9 B, lOKX'aHdIOSt-4'CI1-3-OHC l7-acetate (Formula VII) 3-one (Formula VIII)The compounds according to the invention may be worked up topharmaceutical or veterinarian preparations in the usual way. Thusinjection liquids may be produced by dissolving a methylene chloridesolution of an active compound in arachid oil and by evaporatingmethylenechloride subsequently. Suppositoria may be produced by mixingintimately an active compound with an ester of a higher aliphaticalcohol and a higher aliphatic carboxylic acid, for example carbowaxes,or with cacaobutter or with a mixture of gelatine and glycerol. Furtherthe inventive compounds may be worked up into tablets using the usualfillers such as starch or binders or lubricants for example magnesiumstearate, carboxy methylcellulose and the like.

The compounds according to the invention may for example be prepared byone of the following methods.

1) A 3-keto-4-dehydro-6-fluoroor -6-bromoor -6- chloro- (9B,lOa)-steroidmay be brominated or chlorinated in allylic position with respect to thedouble bond with a suitable halogenating agent, such as for exampleelemental chlorine or bromine, N-bromoor N-chlorosuccinimide,N-dibromoor N-dichlorodimethylhydantoin, N-dichloroorN-dibromo-benzenesulphonamide, or pyridine perbromide or pyridineperchloride.

(2) A 3,5-bisdehydro-3-enolether of a 3-keto-4-dehydro-6-fiuoro (or-6-bromoor -6-chloro-)-(9,B,10a)- steroid may be reacted with achlorinating or a brominat- 3 ing agent as mentioned under (1) above orwith perchloryl fluoride.

Methods of producing the said starting materials have been described inthe literature. The halogenating methods described under (1) and (2)above are methods known per se and are elaborately described in theliterature. In general, any hydroxyl group present is preferably in theprotected form, for example as an etherified or as an esterifiedhydroxyl group, when carrying out the halogenation reaction.

According to the methods as indicated under (1) and 2) above the secondhalogen atom is introduced at carbon atom 6.

When method (2) is applied the 3,5-bisdehydro-3-enol ether grouping isconverted, simultaneously with the introduction of the second halogenatom, into a 3-keto4- dehydro grouping.

The invention further comprises a method of producing3-keto-4,6-bisdehydro-6-fiuoro (or 6-bromoor 6-chloro)-(9B,10a)-steroids in which method 3-keto-4-dehydro-6,6-dihalogeno-(9B,10a)-steroids are used as intermediate or as startingmaterials. In the said 3-keto-4-dehydro-6,6-dihalogeno-(9B,10o)-steroids one halogen atom is taken from the groupconsisting of fluorine, chlorine and bromine and the other halogen atomis taken from the group consisting of chlorine, bromine and iodine.

3-keto-4,6-bisdehydro-6-halo-(9fi,l0a)-steroids have interestingharmacological properties such as progestational or anabolic/androgenicactivities. Hitherto, it has been proposed to prepare these compounds bytreatment of a 3-keto-4-dehydro-6-fiuoro-(9B,l0a)-steroid with2,3-dichloro-S,6-dicyanobenzoquinone or by oxidizing an enolether of a3-keto-4-dehydro-6-halogeno-(-fiuoro, chloro or bromo)-(9 3,10a)-steroidwith MnO Although these methods result to a certain extent in acceptableyields of the desired products a need for further improvement in thisrespect has been evident, and may be achieved by the process accordingto this aspect of the present invention, as devised above, using the3-keto-4- dehydro-6,6-dihalogeno-(9/3,l0a)-steroids as defined on theformer page as starting materials or as intermediates.

In its simplest form this inventive process consists indehydrohalogenating the 3-keto-4-dehydro-6,6-diha1ogeno-(9fl,l0u)-steroid as defined on the former page to produce thecorresponding 3-keto-4-6,6-bisdehydro-6-halogeno-(9 8, 10cc)-St6l'0ld.The dehydrohalogenation step may be carried out in the conventionalmanner e.g. by using an organic amine, for example a tertiary amine suchas pyridine, collidine, dimethylaniline or diethylaniline. It is alsopossible to use finely powdered calcium oxide or lithium halide, forexample LiCl or LiBr in dimethylformarnide, alone or if desired in thepresence of lithium carbonate.

This method provides good yields of the desired 3-keto-4,6-bisdehydro-6-halogeno-(6-fluoro-, chloroor bromo)-(9}3,100c)-St10id$.

Special advantages of this method become apparent when it is combinedwith a process of preparing the starting material of the aforesaidmethod. Such starting materials 3-keto-4-dehydro-6,6-dihalogeno- 96, 10oz -steroids) may be prepared by enoletherification as position 3 of a3-keto-4-dehydro-6-fiuoro (or 6-chloroor 6-bromo)-(9fi,l0a)-steroidfollowed by halogenation (fluorination, chlorination, bromination,iodination). Thus in a more specific form the invention comprises amethod of producing 3 keto-4,6-bisdehydro-6-halogeno (fiuoro-, chloroorbIOmO-)-(9}9,10a)-St6f0id comprising the steps of enoletherification atcarbon atom 3 of a 3-keto-4-dehydro-6-halogeno (fluoro-, chloroorbromo)-(9,6,l0a)- steroid followed by halogenating (chlorinating,brominating or iodinating) the thus produced3-enolether-3,5-bisdehydro-6-halogeno-(95,10cc)-steroid to produce a3-keto- 4-dehydro-6,6-dihalogeno-(9B,l0a)steroid and followed finally bydehydrohalogenating the 6,6-dihalogeno-(9B,- low-steroid.

This process gives relatively high yields of 3-keto-4,6-

4 bisdehydro-G-halogeno (fiuoro-, chloroor bromo-l (9fl,10a)-steroids ascalculated on the basis of 3-keto-4- dehydro-6-halogeno-(fiuoro-,chloroor bromo)-(9fl.- 10oc)-St6I'OldS as starting materials, inparticular when the halogen atom of the starting material is a fluorineatom.

One of the advantages of this 3-step process is that it may be carriedout without working up the intermediately formed products. Thus thehalogenation can be carried out by the addition of the halogenatingagent to the reaction mixture of the enoletherification reaction; andthe dehydrohalogenation reaction may be carried out in the thusresulting reaction mixture.

Enoletherification may conveniently be carried out with an orthoformateester in the presence of a catalyst, e.g. with ethylorthoformate andhydrochloric acid or with ethylorthoformate and p-toluene sulphonicacid.

Halogenation may be effected by means of one of the fluorinating,chlorinating, rominating or iodinating methods described above.Introduction of an iodine atom at carbon atom 6 may be carried out withN-iodo succinimide or with N-iodo-benzenesulphonamide, giving a compoundof Formula IX.

The dehydrohalogenation reaction may take place in the usual manner e.g.with an organic tertiary amine such as collidine, pyridine, dimethylordiethylaniline. It is also possible to use finely powdered calciumoxide, or lithium halide e.g. LiCl or LiBr, in dimethyl formamide. Ingeneral this latter method gives somewhat higher yields than the one inwhich an organic base is used, with or without lithium carbonate alsopresent.

By way of illustration, certain preferred processes embodying theinvention will now be described in more detail in the ensuing specificexamples. In the examples. unless otherwise specified parts orpercentages are weightfor-weight, and temperatures are in degreesCentigrade.

The method according to the invention is in particular of advantage forthe production of 3-keto-4,6-bisdehydro- 6-fiuoro-(9fl, 10cc) -steroids.

In case both 6-halogen atoms are different from each other, it should beborn in mind that HI is more easily split oif than HBr, which lattermolecule is more easily removed than I-ICl. Under conventionalconditions for dehydro halogenation the 6-fiuorine atom is not splitoil, when the other 6-halogeno atom is either chlorine, bromine oriodine from the 6,6-dihalogeno steroids under consideration.

Example 1 A solution of 1.8 gms. of 6,8-bromo-9B,10a-pregn-4-en-3,20-dione and 50 mgms. of p-toluenesulphonic acid in a mixture of 5 ml.of methylene chloride, 20 ml. of purified dry dioxan and 1.2 ml. offreshly distilled ethylorthoformate, was allowed to stand at roomtemperature for 20 hours. After dilution with 300 ml. of petroleum etherand addition of 1 ml. of dry pyridine, the reaction mixture was filteredthrough a column of 20 gms. of silica gel. Elution was completed with200 ml. of a mixture of benzene and petroleum ether (1:3). Thefiltration procedure was repeated through another 20 mgs. of silica gel.After evaporating off the solvents in vacuo, a yield of 0.8 gm. of oily3-ethoxy-6-bromo-9fi,10a-pregna-3,5-dien-20- one was obtained.

The 3-enolether was dissolved in 30 ml. of acetone at 0 C. and was thenbrominated by the successive addition with stirring at 0 C. of asolution of 0.34 gm. of sodium acetate in 3.4 ml. of water, 0.8 gm. ofN-brornosuccinimide and 0.3 ml. of acetic acid. Stirring was continuedfor 30 minutes, and the reaction mixture then worked up by dilution with200 ml. of ice-water and extraction with methylene chloride. The extractwas washed successively with water, a sodium bicarbonate solution, andagain with water. Evaporating off the solvents after addition of 0.1 ml.of pyridine gave oily 6,6-dibromo-9B, 10a-pregn-4-en-3,ZO-dione.

The 6,6-dibromo product was dissolved into 2 ml. of dry pyridine and theresulting solution was heated at C. for 45 minutes. Working up gave 0.8gm. of a crude product, which was chromatographed through a. column of15 gms. of silica gel. The column was eluted with mixtures of benzeneand acetone containing increasing quantities of the latter solvent. Fromthe appropriate fraction 0.4 gm. of impure6-bromo-9fi,10a-pregna-4,6-dien- 3,20-dione was obtained.Recrystallization from ethanol yielded 0.25 gm. of the pure compound.

Melting point: 107l08 C. (dec., vac.), 5(MI18X1II1111'I1 92 m .)=19,000,[a] =-321 (CHClg).

Example 2 1.18 gms. of 6B-bromo-9 3,10u-pregn-4-en-3,20-dione wereetherified in the same manner as described in Example 1. After thereaction mixture had stood for 24 hours, 30 m1. of acetone were addedand the solution obtained was cooled to C. and then brominated withN-bromosuccinimide. The 6,6-dibromo-9fi,10a-pregn-4-en 3,20- dioneobtained was dehydrobrominated and worked up also as described inExample 1. By this procedure the yield of6-bromo-9B,l0u-pregna-4,6-dien-3,20-dione was improved to 0.40 gm.

Example 3 6B-bromo-9fi,lOa-pregn-4-en 3,20 dione was etherified asdescribed in the foregoing Example 2. In this experiment, however, thebromination was carried out by means of bromine in equivalent amounts.After dehydrobromination of the 6,6-dibromo-9/8,10a-pregn-4en-3,20-dione and working up, 0.35 gm. of6-bromo9fi,l0a-pregna-4,6-dien-3,20-dione was obtained.

Example 4 To a solution of 0.814 gm. of 65-chloro-1h-hydroxy-9,9,10a-pregn-4-en-3,20-dione l7-acetate in 15 ml. of dry dixan, therewere added, whilst stirring, 0.7 ml. of ethyl orthoformate and 28 mgms.of p-toluenesulphonic acid. The solution was allowed to stand at roomtemperature in the dark for 22 hours. After cooling to 0 C., 20 ml. ofcold acetone, a solution of 0.2 gm. of dry sodium acetate in 2 ml. ofwater, 0.75 gm. of N-bromosuccinimide and 0.2 ml. of acetic acid wereadded, whilst stirring, to the solution of the 3-enolether in the ordergiven. After stirring for one hour, the reaction mixture was poured outinto water and extracted with benzene-ether. The combined extracts werewashed with a sodium bicarbonate solution and with water. Drying andevaporation of the solvent in vacuo yielded a brownish resin with ana(l%, 1 cm.)=230 at 236.5 m substantially representing6-bromo-6-chloro-17a-hydroxy-9B,10a pregn 4- en-3,20-dione l7-acetate.

A solution of the said resin product in ml. of pyridine was heated atapproximately 95 C. for one hour. Working up in the usual way yielded0.66 gm. of a residue, which was chromotographed through a column of 12gm. of silica gel. From the appropriate fraction 0.48 gm. of 6-chloro17oz hydroxy 93,10 pregna 4,6-diene-3, 20-dione 17-acetate was obtained.Recrystallization from ethanol yielded the pure compounds.

Melting point: 150151 C. (dec.), e( \maximum :286 m;r)=20,800, [a] =-40l(CHCI Example 5 A solution of 9.2 gms. of 65-fluoro-9fi,10a-pregn-4-en-3,20-dione and 0.37 gm. of p-toluenesulphonic acid in 185 ml. of drypurified dioxan and 9.2 ml. of ethyl orthoformate, was allowed to standat room temperature in the dark for 24 hours. The reaction mixture wascooled to 0 C. and 300 ml. of acetone at 0 C. were added. The3-enolether was then brominated by successive addition at 0 C. withstirring, of a solution of 3.4 gm. of sodium acetate in 34 ml. of water,then 8.2 gm. of N-bromosuccinimide, and finally 3 ml. of acetic acid.After stirring at 0 C. for a further 30 minutes, the reaction mixturewas worked up by diluting with 2 litres of ice-water and extracting withmethylene chloride and petroleum ether. The extract was washedsuccessively with water, a sodium bicarbonate solution and again withwater. Evaporation of the solvents after addition of 1 ml. of pyridinegave a residue of 6-bromo-6-fiuoro-9B,10 x pregn 4 en 3,20-dione. Thisresidue was dissolved in 10 ml. of pyridine, and resulting solutionheated at C. for 45 minutes. Workup as usual gave 8.1 gms. of a darkbrown-coloured resin.

Chromatography through a column of 150 gms. of silica gel gave 4.53 gms.of product from the appropriate fraction. Recrystallization from ethanolat -25 C. yielded 3.70 gms. of 6-fluoro-9,8,10a-pregna-4.6-dien3,20dione.

Melting point: 177178.5 C. 45(MI18Xl11lUII1 285 m =23,600. [a] =263(CHCl Example 6 To a solution of 10 gms. of a mixture of 6aand 6 3-fiuoro-l 7 a-hydroxy-9fi,10m-pregn-4-en-3,20-dione 17-acetate in 200 ml.dry purified dioxan were added 10 ml. of ethyl orthoformate and 400mgms. of p-toluenesulphonic acid. After standing at room temperature for24 hours, the reaction mixture was cooled to 0 C., and to it weresubsequently added 300 ml. of acetone at 0 C., a solution of 3.4 gms. ofsodium acetate in 34 ml. of water also cooled to 0 C., 9.2 gms. ofpowdered N-bromosuccinimide and 3.3 ml. of acetic acid. The reactionmixture was stirred at 05 C. for 30 minutes and then worked up. The6-bromo- 6-fiuoro-17a-hydroxy-9B,10a-pregn-4-en-3,20-dione 17-acetateproduct was dehydrohalogenated in approximately 30 ml. of pyridine byheating at 90 C. for one hour. Working up as usual gave 9.26 gms. of aresidue with an a(1%, 1 cm.):438 at 284 m Chromatography through acolumn of 150 gms. of silica gel gave after recrystallization of theappropriate fractions 4.8 gms. of6-fiuorol7a-hydroxy-9fi,10zx-pregna-4,6-diene-3,20-dione 17-acetate.

Melting point: 182.5184.5 C. e(,t maximum=285 m )=24,000.

Example 7 Using the same procedure as described in Example 6, 1 gm. of amixture of 611- and 6/3-fluoro-17ot-hydroxy-9fi,-lOuc-PI6gD-4-6I1-3,2U-dl0n6 l7-acetate was enoletherified. After theaddition of acetone at 0 C., halogenation was carried out with anequivalent amount of N-iodo-succinimide. Work-up, dehydroiodination ofthe 6-iodo-6- fluoro-17a-hydroxy-9B,10a-pregn-4-en-3,20-dione 17-acetatewith collidine, and again working up as described in Example 6, finallygave 0.45 gm. of 6-fluoro-17a-hydroxy-9,8,10u-pregna-4,6-dien-3,20-dione17-acetate.

Example 8 3 gms. of 65-fluoro-175-hydroxy-9f3,10,8-androst-4-en- 3-one17-acetate were dissolved into a solution of mgms. of p-toluenesulphonicacid in a mixture of 60 ml. of dry purified dioxan and 3 ml. of freshlydistilled ethyl orthoformate. The reaction mixture was kept atapproximately 15 C. in the dark for 20 hours, after which it was cooledto 0 C. after the addition of 90 ml. of acetone. Then while stirring 1g. of sodium acetate in 10 ml. of water, 3 gms. of finely powderedN-bromoscuccinimide and 1 ml. of acetic acid were quickly added, in thesequence given, to the solution of the 3-enolether. Stir ring wascontinued at 0 C. for 45 minutes. Thin-layer chromatography of samplesof the reaction mixture at different times of reaction indicated that inabout a quarter of an hour the greatest part of the ether had alreadybeen converted into the brominated product. After working up 10 ml. ofpyridine were added to the residue of6-bromo-6-fiuoro-17B-hydroxy-9,B,10a-androst-4- en-3-one 17-acetate andthe solution was heated at approximately 90 C. for about one hour.

The residue (2.41 gms.) obtained was combined with that obtained fromanother identical experiment starting with 5 gms. ofGB-fluoro-l7fi-hydroxy-9fl,l0a-androst-4- en-3-one 17-acetate. Thecombined residues were dissolved in 2 litres of a mixture ofbenzene-petroleum ether (1:1). This solution was chromatographed througha column of 280 gms. of silica gel. Elution and recrystallization of theappropriate fractions yielded 4.02 gms. of6-fluoro-17B-hydroxy-9B,10a-androsta-4,6-dien-3one 17- acetate.

Melting point: m =23,400.

156158 C. e()\maximum=285 Example 9 1 gm. of6p3-fluoro-17B-hydroxy-913,10a-androst-4-en-3- one l7-acetate wasenoletherified as described in Example 8, and the product worked up asdescribed in Example 1 yielding 0.75 gm. of crude enolether.

To a solution of this enolether fraction in 15 ml. of ether at C. asolution was added of 1.6 gm. of potassium acetate in 30 ml. of 85%aqueous acetic acid. Bromination was carried out by adding withstirring, a solution of 320 mgms. of bromine in 10 ml. of acetic acid inthe course of 5 minutes. After stirring for another 5 minutes thereaction mixture was worked up. The product, 6-bromo-6-fluoro-17,6-hydroxy-9fi,10a-androst-4-en 3 one l7-acetate, wasdissolved into 10 ml. of pyridine and the solution was heated at 90 C.for 50 mintues. Working up yields 510 mgms. of a residue. Purificationby chromatgraphy through a column of silica gel and recrystallizationfrom ethanol at 25 C. finally yielded 6-fiuoro-17p-hydroxy-9/3,10u-androsta-4,6-dien-3-one 17-acetate with amelting point of 151.5-152.5 C. and an a(1%, 1 cm.)=675 at 284 my"Example 10 To a solution of 4 gm. of 6oc-flllOrO-9/3, 10m-pregn-4-en-3,20-dione in 80 ml. of dry, purified dioxan were added 4 ml. of freshlydistilled ethyl orthoformate and 1-60 mgms. of p-toluenesulphonic acid.After standing at room temperature for 24 hours, the reaction mixturewas worked up as described in Example 1, yielding the 3- enolether in anearly quantitative yield. The non-crystalline residue was dissolvedinto 100 ml. of acetone, after which 1.25 gms. of potassium acetate and55 ml. of dry ethanol were added to the solution. While stirringvigorously, perchloryl fluoride was introduced into the solution at +10C. for 2 hours. Working up yielded 3.72 gms. of a resin, which waschromatographed through a column of 120 gms. of silica gel usingbenzene-acetone as the solvents. From this a fraction of 1.43 gms. of6,6- difluoro compound was obtained, which after recrystallization fromacetone-hexane yielded 0.8 gm. of6,6-difluoro-9f3,10a-pregn-4-en-3,20-dione.

Melting point: 155-156 C. mum=229 m .)=12,100.

Example 11 6ot-fluoro-1713-hydroxy-9f3,l0et-androst-4-en 3 one 17-acetate (8.65 gms.) was etherified as described in Example 10. The crudeenolether was treated with perchloryl fluoride and the reaction mixtureworked up. After chromatography and recrystallization fromacetone-hexane at 0 C., 2.17 gms. of6,6-difluoro-17/8-hydroxy-9B,10aandrost-4-en-3-one 17-acetate wereobtained.

Melting point: 189.5191 C. e()\maximum=229 m,u=11,900. [a] =-55 (CHClg).

Infrared absorption bands at: 1742, 1 690, 1630, 1420, 1255, 1125, 1045,1030 and 886 cmr M.M.R.-spectrum: 0.85/s. (3)CH -18; 1.43/d/J=1 Hz.(3)CH -19; 2.05/s. (3)17fi-OAc; 4.73/m. (1)CH-17; 6.26/d/J=3.5 Hz.(1)CH-4.

Example 12 9B,10a-androst-4-en-3,17-dione was converted into the3pyrrolidino-3,S-dienamine by refluxing in methanol in the presence ofpyrrolidine. The crystalline enamine (melting point 123125 C.) was thenreacted with methyl magnesium bromide in tetra-hyd-rofuran (or ether.After hydrolysis with aqueous methanolic potassium hydroxide at 45 C.for one hour the reaction mixture was worked up to give 17,8 hydroxy 17methyl-95,100:- androst-4en-3-one with a melting point of 133-134 C. Thelatter compound was reacted with isopropenylacetate in benzene in thepresence of p-toluenesulphonic acid by refluxing for 4 hours. Work-upand recrystallization yielded 170: methyl-9B,10a-androsta-3,5-dien-3,l7-diol 3,17-diacetate with a melting point of 128-130 C. This diacetatewas chlorinated in a medium of ether aqueous acetic acid with chlorinein the presence of sodium acetate at 5 C. Working up yielded crystalline6B- chloro 17 3 hydroxy 17-methyl-9 8,l0a-androst-4-en-3- one 17-acetatewith a melting point of 168-170 C.

This compound was enoletherified as described in Example 4, and theresulting 3-enolether was bromated without intermediate working up, asdescribed in that example. The resulting6-bromo-6-chloro-17,8-hydroxy-l7- methyl-Qfi,10a-androst-4-en-3-one17-acetate was dehydrobrominated with pyridine at C. for 45 minutes toyield, after working up and recrystallization, 6-chloro- 17,8 hydroxyl7-methyl-9fi,10a-androsta-4,6-dien-3one 17-acetate with a melting pointof 152-153 C.

Example 13 17 oz methyl-9,8,10a-androsta-3,5-dien-3,17-diol3,17-diacetate was fluorinated in acetone-ethanol with perchlorylfluoride in the presence of anhydrous sodium acetate at 0 C. until nomore starting material proved to be present (as determined by thin-layerchromatography). Working up yielded a mixture of 6aand6fi-fluoro-17B-hydroxy 17 methyl 9 3,10a-androst-4-en-3-one 17-acetate.This mixture was enoletherified as described in Example 6. Working up asdescribed in Example 1 gave the oily 3-enolether, which was fluorinatedas described in Example 10. Working up, chromatography andrecrystallization from acetone-hexane finally yielded 6,6-difluoro- 17phydroxy 17 methyl-9p,10u-androst-4-en-3-one 17- acetate withe()\maximum=229 m,u)=12,000.

Hydrolysis of the 17-acetoxy to the 17-hydroxy group can conveniently becarried out by reduction with lithium aluminium hydride intetrahydrofuran subsequently followed by selective reoxidation of the3-hydroxy group with 2,3-dichloro-S,6-dicyanobenzoquinone in order torestore the 3-ket0-4-dehydro system.

Example 14 17a-acetoxyprogesterone was 3-enolesterified by reaction withisopropenyl acetate in benzene in the presence of p-toluene-sulphonicacid by refluxing for 4 hours. The diester product,3,17u-dihydroxy-pregna-3,5-dien-20-one 3, 17-diacetate, was chlorinatedin ether-aqueous acetic acid with chlorine in the presence of sodiumacetate at 5 C. After working up, a mixture of 6aand6,Bchloro-17aacetoxyprogesterone was obtained, which, withoutintermediate purification, was enoletherified and subsequentlybrominated as described in Example 4 to yield the crude 6 bromo 6chloro-l7u-acetoxyprogesterone. Dehydrobromination by heating of thedihalo-product in pyridine at 95 C. for 40 minutes gave, after workingup and purification, 6-chloro-6-dehydro-17a-acetoxy-progesterone with amelting point of 2082l0 C. and e( \maximum =285 m =22,500.

Example 15 6a-fluoro-testosterone 17-propionate (or the corresponding6,3-fluoro compound or a mixture of 6aand 6B- fluoro compounds) (A.Bowers and H. J. Ringold, Tetrahedron 3, 14 (1958)) was enoletherifiedand subsequently brominated as described in Example 5. The crude 6-bromo6-fluoro-testosterone 17-propionate was dehydrobrominated byheating in 20 ml. of pyridine at 95 C. for one hour. Working up andpurification gave 5.9 gms. of 6-fluoro6-dehydrotestosterone17-propionate with a melting point of 122-124 C. and an e( \maximum=284m )=23,700.

Example 16 By the method described in Example 15, 6-fluoro17macetoxy-progesterone grns.) (A. Bowers et al., J. Am. Chem. Soc. 81,5991 (1959)) was enoletherified, brominated and dehydrobrominated toyield 2.97 gms. of 6- fiuoro-6-dehydro-l7a-acetoxy progesterone with amelting point of 227-230 C. and e()\maximum=284 mg) =24,- O00.

Whereas certain preferred processes and methods of practising theinvention have been described in the aforegoing specific examples, itwill be understood that modifications may be made in the proceduresdescribed, within the scope of the invention, as will be apparent tothose skilled in the art, whether in producing the same compounds orother compounds of Formula I as herein defined. In particular,etherification or esterification of a free hydroxyl group represented byR or R' Or saponification or de-etherification of such hydroxy group soprotected, may be effected in known manner at a convenient point in thereaction sequence. Likewise a hydrocarbon radical represent by R may bepresent in the starting material or may be introduced at a suitablereaction stage. When desired, a l-dehydro double bond may be introducedinto the steroid nucleons in known manner at a suitable stage.

Example 17 6a-fil101'0 175 hydroxy 9 3,10cz androst-4en-3-one l7-acetateg.) was enoletherified as given in Example 1. Work-up gave 15 .43 g. 3,5bisdehydro 3 enolether, which was halogenated with N-chlorosuccinimideas described in Example 1. Work-up gave 15.44 g. of an oil, which wascarefully chromatographed through a column of 300 g. of silicagel.Rechromatography of the 6-chloro, 6-fiuoro fraction through a column of250 g. of silicagel finally afforded both 6-chloro, 6-fiuoro isomers ina pure state after recystallization of the appropriate fractions fromether.

The analytical data of 6a-chl0r0-6-fiu0r0-17B-hydroxy-95,10a-androst-4-en-3-one 17-acetate are the following:

M.P. 145146 e( \maximum=237 m )=l3,200. [a] =--32 (chloroform).

Those for 6/3 chloro-6-fluoro-17B-hydroxy-9p3,10u-androst-4-en-3-one17-acetate are: M.P. 150.5152. e( \maximum=237 m r)=11,l50. [a] :86(chloroform).

Example 18 6fi-chloro-17B-hydroxy-9fi,10u-androst-4-en 3 one 17- acetate(5.16 g.) was enoletherified and worked up as described in Example 1.The 3-enolether obtained (5.4 g.) was dissolved into 100 ml. of acetoneand to this solution at 0 was added a solution of 2.7 g. of drypotassium acetate in 70 ml. of dry ethanol. Then, with vigorousstirring, a mixture of purified perchloryl fluoride and nitrogen (1+1)was led into the solution at 0. Work-up after two hours afforded a crudeproduct, which was chromatographed through a column of 110 g. ofsilicagel. Rechrornatography of the appropriate fraction afforded thepure a-chloro-6-fluoro-l7fi-hydroxy-9/3,10aandrost-4-en-3-one 17-acetateand 6fi-chloro-6-fluoro-17fihydroxy-9,6,10a-androst-4-en-3-onel7-acetate.

Example 19 A mixture of 60cand6,8-fluoro-17B-hydroxy-9B-10aandrost-4-en-3-one l7-acetate (19 g.) wasenoletherified as described in Example 1. The 3-enolether obtained wasdissolved in 660 ml. acetone at 0". Subsequently were added to thissolution a solution of 7.15 g. of sodium acetate in 71 ml. of water,19.4 g. of N-bromosuccinimide and finally 71 ml. of acetic acid.Stirring was continued at 0.5 for 2 /2 hours. Work-up gave 23.9 g. of aresidue, which was crystallized from ether to give 6.7 g. of 65- bromo,6-fluoro 17,8 hydroxy-9,8,10a-andr0st-4-en-3-one 17-acetate with amelting point of 104105 (dec.) e()\ maximum=250 m )=8200. [u]; 168 (CHClChromatography of the mother-liquor through a column of 250 g. ofsilicagel afforded 1.62 g. of 6a-bromo,6-fluoro-17fl-hydroxy-9B,l0a-androst-4-en-3-one 17-acetate with a melting pointof 113-116 (dec.) and e()\ maximum=245 m )'=l1,650. [or] '=+5 (CHClExample 20 a-chloro, 6-fluoro-17,8-hydroxy-9B,10a-androst-4-en-3- onel7-acetate (100 mg.) in a solution of 33 mg. of lithium chloride in 13ml. of dimethyl formamide was heated at 75 for 7 hours. Work-up gave ina yield of the 6-fluoro-9B,10a-androsta-4,6-dien-3-one l7-acetate.

Example 21 fiwchloro-ti-fiuoro-17fi-hydroxy-9B,10u-andr0st 4 en- 3-one17-acetate (600 mg.) was heated in 60 ml. of refluxing collidine for 7hours. Work-up afforded in a yield of 77% the6-fluoro-9fl,10a-androsta-4,6-dien-3-one 17- acetate.

Example 22 According to Examples 20 and 21 were dehydro halogenated to6-fluoro-9/3,l0a-androsta-4,6-dien 3 one 17- acetate the followingcompounds:

6,8-chloro, 6-fluoro-17B-hydroxy-9/3,10a-androst-4-en-3- one 17-acetate6B-bromo, 6-fluoro-17fl-hydroxy-9/3,10a-androst-4-en-3- one 17-acetate6cc-10d0, 6-fiuoro-17fi-hydroxy-95,10a-andIost-4-en-3- one 17-acetateExample 23 A mixture of 6a-fiuoroand 6-B-fluoro-17fi-hydroxy-9fl,l0a-androst-4en-3-one 17-acetate (1 g.) was enoletherified asdescribed in Example 1.

After standing at room temperature for 20 hours, the reaction mixturewas diluted with acetone at 0 and then halogenated withN-iodosuccinimide as described in Example 1 for N-bromo-succinimide.Work-up afiorded 6- iodo,6-fluoro-l7fi-hydroxy-9fl,l0a-androst-4-en-3-one 17- acetate.Dehydrohalogenation according to Example 20 afiorded 650 mg. of 6 fluoro17,8 hydroxy 95,100:- androsta-4,6-dien-3-one 17-acetate.

Example 24 Injection liquids of6,6-difiuoro-17B-hydroxy-9fi,10aandrost-4-en-3-one 17-acetate (activeingredient) were made as follows.

5.00 g. of the active ingredient were dissolved in mls. of a solution of2% w./v. 'benzylalcohol and 46% w./v. benzylbenzoate in ricinic oil at atemperature of 60 C. The solution was cooled to room temperature andreplenished to mls. with the ricinic oil solution aforesaid. The mixtureWas homogenised by stirring and filtrated. Ampoules and vials werefilled with the filtrated solution, subsequently sealed and thensterilised by heating for one hour at Example 25 2 g. of6,6-difiuoro-9/3,l0a-pregn-4-ene-3,20-dione were dissolved inchloroform, which solution was mixed homogeneously with 194 g. oflactose. The mixture was dried at 40 C. during 1 hour. The mixture waswetted with a 10% aqueous solution of 2 g. of gelatine and subsequentlyground through a 20 mesh sieve. The mixture was dried at 40 C. during 24hours, whereupon the granules were ground through a 20 mesh sieve. Themixture was weighed and then had added to it proportional amounts oftalcum venetum and magnesium stearate in amounts of optimal 25 mg. and 2mg. respectively. The resulting mixture was homogenised and worked totablets of 225 mg. each.

We claim: 1. A steroid compound of the formula Ha h Hal: wherein thesteroid nucleus has a configuration selected from the group consistingof the 9 8, 100: steroids and the 90:, 1018 steroids, carbon atoms 1 and2 are joined by a single or double carbon to carbon bond, wherein Haland Hal are each halogen atoms selected from the group consisting ofbromine, chlorine and fluorine with the proviso that at least one ofsaid atoms is other than fluorine, R is selected from the groupconsisting of hydroxy, acyloxy of 1 to 20 carbon atoms, said acyloxymoiety being the acyloxy moiety of a carboxylic acid selected from thegroup consisting of saturated or unsaturated aliphatic carboxylic acidsof 1-20 carbon atoms, benzoic acid, p-hexyloxy-phenylpropionic acid,hexahydrobenzoic acid, phenylacetic acid, 5 cyclopentylpropionic acidand B-cyclohexylpropionic acid, and etherified hydroxy of 1 to carbonatoms and the moiety and wherein R' is selected from the groupconsisting of hydrogen and alkyl of l to 6 carbon atoms when R is otherthan the moiety. i

2. A compound of claim 1 of the formula CH3 CH2 (3:0

3. A compound of claim 1 of the formula CH3 C=O I--O Acetate 4. Acompound of claim 1 of the formula 5. A compound of claim l of theformula 5 CH3 CH3 0 0 Acetate (Lt I 6. A compound of claim 1 of theformula 3H3 CH3 0 Acetate 7. A compound of claim 1 of the formula 8. Acompound of claim 1 of the formula H CH3 o-o-om-om Br F 9. A compound ofclaim 1 of the formula CH; 0 Acetate 13 14 10. A compound of claim 1 ofthe formula 13. A compound of claim 1 of the formula CH: (\l I l i l l ll\/\/ l H O 11 A compound of claim 1 of the formula a m m e o w m m f Iw B 1 w H m G :I F c a o o --O Acetate CH; O Acetate O Acetate l H M 15.A compound of claim 1 of the formula References Cited UNITED STATESPATENTS 3,219,673 11/1965 Boswell 260397.3

LEWIS GOTTS, Primary Examiner E. C. LOVE, Assistant Examiner US. 01.X.R.

zen-239.5, 397.4, 397.5; 42-242, 243

mg? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,468,917 Dated September 23,1969

Inventor(s) PIETER WESTERHOF ET AL It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 3, line 45, "4-6,6" should read 4,6

Column 4, line 48, "1.8" should read 1.18

Column 6, line 54, "105" should read 10d Column 9, line 23, "representshould read represented Column 12, claim 6, change the formula to read:

I CH 0 Acetate Column 12, claim 7 change the formula to read: CH 0Acetate 0 B Cl Column 14, claim 13, change the formulgzito read:

CH3 O r! L I r Signed and sealed this 7 ay of July 1970. (SEAL) AttestEDWARD M.FLETCHER,JR. WILLIAM SCHUYLER,

Attesting Offi Commissioner of Patents 'zg ggg UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Patent No. 3, 68,919 Dated September23, 1969 znvent John R. Kilsheimer and Ross A. Kremer It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

0 mm ine e c a m re erence numera 5 cu d c1 a1 64 th 11 f l"9"hl read--6--.

SIGNED KND SEALED JUN 3 0 1970 mm! ET'SGHUYIMYJR- EdwudMFletcherJr.Gomissidner of Patents AneflingOffioer

